Schizophrenia is a chronic neurological disorder that affects approximately 1% of the world population and causes > $60 billion dollars of direct and indirect societal costs in the US alone (Wu et al., 2005). Current therapies to treat this disorder have been effective in ameliorating positive symptoms (hallucinations, delusions, irrational fear), but are less effective in controlling negative symptoms (social withdrawal, anhedonia) and cognitive dysfunction (diminished learning and social cognition). Furthermore, many of the current antipsychotics can cause extrapyramidal side effects (EPS), metabolic syndrome (weight gain), and increased cardiovascular risk liabilities. Due to the inability to control the fll spectrum of symptoms with today's medicines schizophrenia remains a serious medical problem requiring the identification of alternative targets for pharmacological intervention. Glutamate receptor hypofunction has emerged as an hypothesis to more fully understand and treat schizophrenia. This hypothesis was based initially upon observations that N-methyl-D-aspartate (NMDA) receptor channel blockers such as phencyclidine (PCP) can induce a psychological state indistinguishable from some features of schizophrenia in man and in animal models. Thus, augmentation of NMDA receptor function has emerged as an attractive hypothesis as a therapy for schizophrenia. Recently, a small molecule CIQ, (3- chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1 H)-yl)methanone) was identified that selectively potentiates GluN2C and GluN2D containing NMDA receptors by 2-fold. GluN2C and GluN2D subunits are targets of particular interest in that their expression profile in forebrain is limited largely to a subset of hippocampal and cortical interneurons and that circuit-based models of schizophrenia predict that enhancement of interneuron activity driven by GluN2C/2D selective potentiators may be particularly efficacious. Based on these recent findings, we propose to discover and develop novel GluN2C/2D selective potentiators for use as antipsychotics in the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating mental illness that affects millions of Americans. Current medicines for schizophrenia provide only partial improvement and often have serious side effects. The goal of this project is to develop better medicines to improve the quality of life for schizophrenia patients.